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United States Patent |
5,177,104
|
Varma
,   et al.
|
January 5, 1993
|
6-.alpha.-hydroxy derivatives of mevinic acids
Abstract
Compounds of the formula
##STR1##
and pharmaceutically acceptable salts thereof have been found to possess
activity as cell-selective HMG-CoA reductase inhibitors, thus making them
useful as antihypercholesterolemic agents. In the above formula,
##STR2##
R.sup.1 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl; and R.sup.2 is
hydrogen, alkyl, ammonium, or alkali metal.
Inventors:
|
Varma; Ravi K. (Belle Mead, NJ);
Chao; Sam T. (East Windsor, NJ);
Gordon; Eric M. (Pennington, NJ)
|
Assignee:
|
E. R. Squibb & Sons, Inc. (Princeton, NJ)
|
Appl. No.:
|
503576 |
Filed:
|
April 3, 1990 |
Current U.S. Class: |
514/460; 514/548; 514/824; 549/292; 560/119 |
Intern'l Class: |
A61K 031/365; C07D 309/30; C07C 069/74 |
Field of Search: |
549/292
560/119
514/824,460
|
References Cited
U.S. Patent Documents
4346227 | Aug., 1982 | Terahara et al. | 560/119.
|
4410629 | Oct., 1983 | Terahara et al. | 435/146.
|
4444784 | Apr., 1984 | Hoffman et al. | 424/279.
|
4448979 | May., 1984 | Terahara et al. | 549/292.
|
4450171 | May., 1984 | Hoffman et al. | 424/279.
|
4868210 | Sep., 1989 | Trivedi | 514/824.
|
Foreign Patent Documents |
0065835 | Dec., 1982 | EP.
| |
0137444 | Apr., 1985 | EP.
| |
0306210 | Mar., 1989 | EP.
| |
2075013A | Nov., 1981 | GB.
| |
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Owens; Amelia A.
Attorney, Agent or Firm: Gaul; Timothy J.
Claims
We claim:
1. A compound of the formula
and pharmaceutically acceptable salts thereof, wherein
##STR18##
R.sub.1 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl; R.sup.2 is
hydrogen, alkyl, ammonium, or alkali metal;
"alkyl" refers to straight and branched chain groups of up to twelve
carbons;
"cycloalkyl" refers to cyclic hydrocarbon groups of three to twelve
carbons; and
"aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups of six
to ten carbons.
2. The compound of claim 1, wherein R.sup.1 is hydrogen or alkyl.
3. The compound of claim 1, wherein R.sup.1 is methyl.
4. The compound of claim 1, wherein
Z is
##STR19##
and R.sup.2 is hydrogen or alkali metal.
5. The compound of claim 1, wherein
Z is
##STR20##
and R.sup.2 is lithium.
6. The compounds of claim 1 having the names:
[1S-[1.alpha.,3.alpha.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8.beta.]]-2,2-Dim
ethylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-[tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y
l]ethyl]-1-naphthalenyl ester;
[1S-[1.alpha.(.beta.S*,.DELTA.S*),2.alpha.,4.alpha..beta.,6.beta.,8.beta.,8
a.beta.]]-Decahydro-.beta.,.DELTA.,
6-trihydroxy-2-methyl-8-(1-methylpropylcarbonyloxy)-1-naphthaleneheptanoic
acid, monolithium salt;
[1S-[1.alpha.,3.alpha.,4a.alpha.,
7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2-Methylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y
l) -ethyl]-1-naphthalenyl ester, partially racemized; and
[1S-[1.alpha.(.beta.S*,
.DELTA.S*),2.alpha.,4.alpha..beta.,6.beta.,8.beta.,8a.alpha.]]-Decahydro-.
beta.,.DELTA.,6-trihydroxy-2methyl-8-(2-dimethyl-1-oxobutoxy)-1-naphthalene
heptanoic acid, monolithium salt.
7. A hypocholesterolemic or hypolipidemic composition comprising a compound
as defined in claim 1 and a pharmaceutically acceptable carrier therefor.
8. A process for preparing a compound of the formula
##STR21##
which comprises treating a compound of the formula
##STR22##
with a base selected from 2,6-lutidine, collidine, pyridine, quinoline,
2-methylquinoline, sodium bicarbonate and potassium bicarbonate and
sulfonic anhydride, wherein:
R.sup.1 is hydrogen, alkyl cycloalkyl, aryl, or arylalkyl; and
Pro.sup.2 is a protecting group.
9. The process of claim 8, wherein the base is 2,6-lutidine.
10. The process of claim 8, wherein the protecting group is
benzyloxymethyl.
11. A process for preparing a product of the formula
##STR23##
which comprises: (a) treating a compound of the formula
##STR24##
wherein Pro.sup.2 is a protecting group with a base selected from
2,6-lutidine, collidine, pyridine, quinoline, 2-methylquinoline, sodium
bicarbonate and potassium bicarbonate and a sulfonic anhydride to form an
alpha-hydroxy intermediate of the formula
##STR25##
(b) deprotecting the alpha-hydroxy intermediate in the presence of a
catalyst to form the product;
wherein R.sup.1 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl.
12. The process of claim 11, wherein the base is 2,6-lutidine.
13. The process of claim 11, wherein Pro.sup.2 is benzyloxymethyl.
14. A process for preparing a product of the formula
##STR26##
which comprises: (a) treating a compound of the formula
##STR27##
wherein Pro.sup.2 is a protecting group with an organic base selected
from 2,6-lutidine, collidine, pyridine, quinoline, 2-methylquinoline,
sodium bicarbonate and potassium bicarbonate, and a sulfonic anhydride to
form an alpha-hydroxy intermediate of the formula
##STR28##
(b) deprotecting the alpha-hydroxy intermediate in the presence of a
catalyst to form a lactone of the formula
##STR29##
(c) hydrolyzing the lactone with an aqueous ammonium or alkali metal base
to form the product;
wherein:
R.sup.1 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl; and
R.sup.2 is hydrogen, alkyl, ammonium, or alkali metal.
15. The process of claim 14, wherein the organic base is 2,6-lutidine.
16. The process of claim 14, wherein Pro.sup.2 is benzyloxymethyl.
Description
FIELD OF THE INVENTION
The present invention relates to 6-.alpha.-hydroxy mevinic acid
derivatives, which are HMG-CoA reductase inhibitors useful as
antihypercholesterolemic agents, and to methods of use for such compounds.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, compounds of the formula
##STR3##
and pharmaceutically acceptable salts thereof have been found to possess
activity as HMG-CoA reductase inhibitors, thus making such compounds
useful as antihypercholesterolemic agents. In formula I and throughout
this specification, the above symbols are defined as follows:
##STR4##
R.sup.1 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl; and
R.sup.2 is hydrogen, alkyl, ammonium, or alkali metal (such as Na, Li, or
K).
Novel processes for preparing Compound I and an intermediate thereof also
form an integral part of this invention.
DETAILED DESCRIPTION OF THE INVENTION
Listed below are definitions of various terms used to describe this
invention. These definitions apply to the terms as they are used
throughout this specification (unless otherwise limited in specific
instances) either individually or as part of a larger group.
The term "alkyl" or "alk" includes both straight and branched chain
radicals of up to 12 carbons, preferably 1 to 8 carbons. Exemplary alkyl
groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,
pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,
2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various
branched chain isomers thereof, and the like. The term "alkyl" or "alk"
also includes such groups having a halo-substituent, such as F, Br, Cl or
I or CF.sub.3, an alkoxy substituent, an aryl substituent, an alkyl-aryl
substituent, a haloaryl substituent, a cycloalkyl substituent or an
alkyl-cycloalkyl substituent.
The term "cycloalkyl" includes saturated cyclic hydrocarbon groups
containing 3 to 12 carbons, preferably 3 to 8 carbons, which include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclodecyl and cyclododecyl, wherein such groups may be substituted with 1
or 2 halogens, 1 or 2 lower alkyl groups and/or 1 or 2 lower alkoxy
groups.
The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic
aromatic groups containing from 6 to 10 carbons in the ring portion, such
as phenyl, naphthyl, substituted phenyl or substituted naphthyl, wherein
the substituent on either the phenyl or naphthyl may be 1 or 2 lower alkyl
groups, 1 or 2 halogens (Cl, Br or F), and/or 1 or 2 lower alkoxy groups.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and
iodine, as well as trifluoromethyl.
Preferred compounds of formula I are those wherein:
R.sup.1 is hydrogen or alkyl (methyl most preferred);
Z is
##STR5##
and
R.sup.2 is hyd or alkali metal (lithium most preferred).
The compounds of formula I will be formulated with a pharmaceutical vehicle
or diluent. The pharmaceutical composition can be formulated in a
classical manner with solid or liquid vehicles or diluents and
pharmaceutical additives appropriate to the desired mode of
administration. The compounds can be administered by an oral route (e.g.,
tablets, capsules, granules or powders) or a parenteral route (e.g.,
injectable preparations).
A typical capsule for oral administration contains active ingredients (25
mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed
through a 60-mesh sieve and packed into a No. 1 gelatin capsule.
A typical injectable preparation is produced by asceptically placing 25 mg
of a water-soluble salt of sterile active ingredient into a vial,
asceptically freeze-drying and sealing. For use, the contents of the vial
are mixed with 2 ml of physiological saline, to produce an injectable
preparation.
The compounds of the invention are inhibitors of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase and inhibit cholesterol biosynthesis. An
important property of the compounds of the present invention is that they
act more selectively in the cells of the target organ (liver) than in the
cells of other organs or tissues.
Such compounds are useful in treating atherosclerosis to inhibit
progression of disease, in treating hyperlipidemia to inhibit development
of atherosclerosis, and in treating nephrotic hyperlipidemia. In addition,
the compounds of the invention increase plasma high density lipoprotein
cholesterol levels. As HMG-CoA reductase inhibitors, the compounds of the
invention may also be useful in inhibiting formation of gallstones and in
treating tumors.
The compounds of the present invention may also be employed in combination
with antihyperlipoproteinemic agents, such as probucol, and/or with one or
more serum cholesterol lowering agents such as Lopid.RTM. (gemfibrozil),
bile acid sequestrants such as cholestyramine, colestipol,
DEAE-Sephadex.RTM. as well as clofibrate, nicotinic acid and its
derivatives, neomycin, p-aminosalicylic acid, lovastatin, pravastatin,
visinolin (velostatin, symvastatin or sinvinolin) and the like, and/or one
or more squalene synthetase inhibitors.
The above compounds to be employed in combination with the HMG-CoA
reductase inhibitor of the invention will be used in amounts as indicated
in the Physicians' Desk Reference (PDR).
The dose to be administered depends on the unitary dose, the symptoms, and
the age and the body weight of the patient. A dose for adults is
preferably between 20 and 2,000 mg per day, which can be administered in a
single dose or in the form of individual divided doses from 1-4 times per
day.
The compounds of this invention also have useful antifungal activities. For
example, they may be used to control strains of Penicillium sp.,
Aspergillus niger, Cladosporium sp., Cochliobolus miyabeorus and
Helminthosporium cynodnotis. For those utilities they are admixed with
suitable formulating agents, powders, emulsifying agents or solvents (such
as aqueous ethanol) and sprayed or dusted on the plants to be protected.
In addition, the compounds of the invention may also be useful in elevating
HDL-cholesterol levels while lowering levels of LDL-cholesterol and serum
triglycerides.
Compounds of formula I can be prepared by the following exemplary process.
Preparation of the compound
##STR6##
is described in U.S. Pat. Nos. 3,983,140 and 4,346,227. In the process of
forming compound I, compound II is placed in an inert solvent (e.g.,
tetrahydrofuran or dichloromethane) under an inert atmosphere (e.g., argon
or nitrogen) at a temperature of about 15 to 25.degree. C. and treated
with an appropriate silyl protecting agent (e.g., t-butyldimethylsilyl
chloride, triethylsilyl chloride, or phenyldimethylsilyl chloride) in the
presence of an appropriate amine base (e.g., imidazole) to form
##STR7##
where Pro.sup.1 is a silyl oxygen-protecting group such as
##STR8##
and the like.
Compound III is hydrogenated (e.g., with hydrogen gas) in an organic
solvent (e.g., ethyl acetate) in the presence of a catalyst (e.g.,
platinum on carbon) to form a compound of the formula
##STR9##
Compound IV is treated with a base (e.g., potassium hydroxide) in a mixture
of water and an organic solvent such as toluene (optionally containing
some methanol) to form the potassium salt
##STR10##
The potassium salt V is reacted in an organic solvent such as
tetrahydrofuran with an organic base (e.g., pyrrolidine or piperidine) and
n-butyllithium and an alkylating agent (e.g., iodomethane) in an inert
atmosphere (e.g., argon) at about -60.degree. to -20.degree. C. The
resulting amide product is acidified, isolated and heated to about
100-110.degree. C. in an organic solvent (e.g., toluene) to form
##STR11##
in which R.sup.1 is methyl.
Compound VI is oxygen-protected by, for example, reaction with a protecting
agent (e.g., benzyl bromomethyl ether) in the presence of an amine base
(e.g., N,N-dimethylaniline) in an organic solvent (e.g., methylene
chloride) to form
##STR12##
where Pro.sup.2 is a different protecting group from Pro.sup.1 and may be
selected from benzyloxymethyl (which is preferred),
paramethoxybenzyloxymethyl, tetrahydrylpyranyloxy, lower acyl and the
like.
Pro.sup.1 can then be removed by, for example, reaction with a deprotecting
agent (e.g., hydrogen fluoride-pyridine) at about -10 to 10.degree. C.
under an inert atmosphere (e.g., nitrogen) in an inert solvent (e.g.,
acetonitrile) to form
##STR13##
The isomeric configuration of the hydroxyl group in the 6-position is then
changed by, for example, treatment with a weakly nucleophilic organic base
and a sulfonic anhydride (e.g., trifluoromethane sulfonic anhydride) in an
organic solvent (e.g., methylene chloride) at about 0.degree. to
30.degree. C. to form
##STR14##
Examples of weakly nucleophilic organic bases are 2,6-lutidine (which is
preferred), collidine, pyridine, quinoline, 2-methylquinoline, sodium
bicarbonate, potassium bicarbonate, and the like.
Pro.sup.2 is then deprotected (e.g., by hydrogen gas treatment) in an
organic solvent (e.g., ethyl acetate) in the presence of a catalyst (e.g.
palladium hydroxide on carbon) at about 20 to 30.degree. to form Compound
I wherein Z is the cyclized lactone
##STR15##
Alternatively, to form Compound I wherein R.sup.1 is hydrogen, Compound III
is (1) placed in a degassed suspension of a metal catalyst (e.g., platinum
on carbon in an inert organic solvent (e.g., ethyl acetate of
tetrahydrofuran), (2) subjected to hydrogen gas under a pressure of about
30 to 60 psi, and (3) oxygen-protected as described above (Compound
VI.fwdarw.Compound VII) to form Compound VII wherein R.sup.1 is hydrogen.
Compound VII is also oxygen-deprotected as described above (Compound
VII.fwdarw.Compound VIII) to give Compound VIII wherein R.sup.1 is
hydrogen. Compound VIII wherein R.sup.1 is hydrogen can then be (1)
reacted with a sulfonic anhydride as described above to give Compound IX
wherein R.sup.1 is hydrogen and (2) oxygen-deprotected to give Compound I
wherein R.sup.1 is hydrogen.
Compound I wherein Z is the lactone may be converted to the open-chain form
by hydrolysis with an aqueous ammonium or alkali metal base (e.g., lithium
hydroxide) at about 20 to 30.degree. C. in an inert solvent (e.g.,
tetrahydrofuran). R.sup.2 can be converted to hydrogen by treatment with a
mild aqueous acid (e.g., potassium bisulfate).
The following working examples represent preferred embodiments of the
invention. Unless otherwise specified, all temperatures are in degrees
Celsius (.degree.C.). The preparation of each compound appears below its
name. As a shorthand reference, the compound prepared in part 1A will be
called "Compound 1A" or "Intermediate 1A" and so forth for all compounds
hereafter.
EXAMPLE 1
[1S-[1.alpha.,3.alpha.,4a.alpha.,7
.beta.,8.beta.(2S*,4S*),8.beta.]]-2,2-Dimethylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-[tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y
l]ethyl]-1-naphthalenyl ester
1A. [1S-[1.alpha.(R*),3.beta.,4.beta.,7.beta.,
8.beta.(2S*,4S*),8a.beta.]]-2-Methylbutanoic acid, 3-[[(1,
1-dimethylethyl) dimethylsilyl]oxy]-1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(
tetrahydro-4-hydroxy-6-oxo-2H-pyran -2-yl)ethyl]-1-naphthalenyl ester
The starting material for preparation of intermediate A was
[1S-[1.alpha.(R*),3.beta.,4.beta.,7.beta.,8.beta.(2S*,
4S*),8a.beta.]]-2-methylbutanoic acid,
3-hydroxy-1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo
-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester. Preparation of this starting
material has been described in U.S. Pat. Nos. 3,983,140 and 4,346,227.
A solution of 8.43 g (20.7 mmol, 1.00 eq.) of the starting material in 80
ml of dry tetrahydrofuran under argon at ambient temperature was treated
with 1.76 g (25.9 mmol, 1.25 eq.) of imidazole, followed by 3.44 g (22.8
mmol, 1.10 eq.) of t-butyldimethylsilyl chloride. A white precipitate
formed almost immediately (5-10 sec). After stirring for 26 hours, the
reaction mixture was diluted with 80 ml of ether, filtered and
concentrated in vacuo. Purification of the residue by flash chromatography
(with Merck silica gel; 40% ethyl acetate in hexanes) gave 7.41 g (a 69%
yield) of the mono-silylated product (intermediate A) as a white solid,
with a melting point of 111 to 115.degree. C. (More typical yields for
this conversion are in the range of 80 to 85%).
1B. [1S-[1.alpha.(R*),3.beta.,4.alpha..alpha., 7.beta.,8.beta.(2S*,4S*),
8.alpha..beta.]]-2-Methylbutanoic acid, 3-[[(1,1-dimethylethyl)
dimethylsilyl]oxy]decahydro-
7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl
]-1-naphthalenyl ester
To a degassed, argon-purged solution of 9.38 g, 18.0 mmol) of Compound 1A
in 200 ml of ethyl acetate was added 1.4 g of 10% platinum on carbon. This
suspension was subjected to 50 psi of H.sub.2 in a Parr hydrogenation
apparatus for 14.5 hours (overnight). Thin layer chromatography analysis
indicated the complete consumption of starting material with generation of
the desired product and some disilylated product. The filtered reaction
mixture was concentrated and the products were isolated by flash
chromatography. Elution with 45% hexanes in ethyl acetate gave 7.73 g
(82%) of Compound 1B as a clear glass and elution with 30% hexanes in
ethyl acetate gave 0.98 g (13%) of desilyated product.
1C.
[1.alpha.,3.beta.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2,2-Dimeth
ylbutanoic acid,
3-[[(1,1-dimethylethyl)dimethylsilyl]oxydecahydro-7-methyl-8-[2-(tetrahydr
o-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester
A solution of Compound 1B (10.5 g, 20.04 mmol) in a mixture of toluene (200
ml) and methanol (42 ml) was treated with 1.0 N potassium hydroxide (20
ml) at room temperature under an atmosphere of nitrogen for 45 minutes.
The solvent was evaporated in vacuo to give a gum. This was azeotroped
with benzene (250 ml) and then dried in vacuo at 45.degree. (oil bath
temperature) overnight to give a foamy solid.
To a chilled (-55.degree., acetonitrile-Dry ice bath) and stirred solution
of the above solid in dry tetrahydron (150 ml) under an atmosphere of
nitrogen was added dry pyrrolidine (6.48 ml, 77.63 mmol), followed
n-butyllithium (2.5 M in hexane, 27.84 ml, 69.6 mmol). The mixture was
gradually warmed up to -25.degree. (carbon tetrachloride-Dry ice bath) and
stirred for 2.5 hours. Iodomethane (3.12 ml, 50.12 mmol) was added
dropwise. After 1.0 hour, a small aliquot was worked up. .sup.1 H-NMR
spectrum indicated there was 15-20% non-methylated starting material.
Therefore, the mixture was recooled to -55.degree., more dry pyrrolidine
(3.24 ml) and n-butyllithium (2.5 M in hexane, 13.92 ml) were added and
the mixture was warmed up to -25.degree.. After 2.5 hours, iodomethane
(1.56 ml) was added and stirred for another hour. The resulting mixture
was quenched with 10% potassium bisulfate solution (100 ml) at -25
.degree., warmed up to room temperature, saturated with sodium chloride
and extracted with ethyl acetate (3.times.100 ml). The combined ethyl
acetate extracts were washed with a small amount of 5% sodium thiosulfate
solution and brine, dried over anhydrous sodium sulfate and evaporated in
vacuo to give a gummy residue (11.0 g).
The above gum was refluxed in dry toluene (200 ml) under an atmosphere of
nitrogen for 4.0 hours. The solvent was then evaporated in vacuo to give a
gummy material. This material was chromatographed on a column of silica
gel (LPS-1, 450 g) eluting with ethyl acetate-hexane (1:3) to give 7.3g
(67.5%) of Compound 1C as a gum with consistent .sup.1 H-NMR and .sup.13
C-NMR spectra.
1D.
[1S-1.alpha.,3.beta.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2,2-Dim
ethylbutanoic acid, 3-[[1,1-dimethylethyl)
dimethylsilyl]oxydecahydro-7-methyl-8-2-[tetrahydro-6-oxo-4-(phenylmethoxy
)methoxy]-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
To a chilled (0.degree., ice bath) and stirred solution of Compound 1C (7.3
g, 13.52 mmol) in dry dichloromethane (80 ml) under an atmosphere of
nitrogen was added dry N,N-dimethylaniline (3.7 g, 30.53 mmol). After 15
minutes, benzyl bromomethyl ether (5.62 g, 26.13 mmol) was added. The
resulting solution was gradually warmed up to room temperature and stirred
for 20 hours. The solvent was partially removed in vacuo. Ethyl acetate
(300 ml) was added. The ethyl acetate solution was washed with a 10%
potassium bisulfate solution, a saturated sodium bicarbonate solution and
brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give
an oil. This oil was chromatographed on a column of silica gel (LPS-1, 300
g) eluting with ethyl acetate-hexane (1:9) to give 8.5 g (95.4%) of
Compound 1D as an oil with consistent .sup.1 H-NMR and .sup.13 C-NMR
spectra
1E.
[1S-[1.alpha.,3.beta.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2,2-Di
methylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-[tetrahydro-6-oxo-4-[(phenyl-methoxy)
methoxy]-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
A solution of Compound 1D (8.5 g, 12.9 mmol) in dry acetonitrile (100 ml)
was cooled to 0.degree. (ice bath) under an atmosphere of nitrogen and
treated with two 4-ml portions of hydrogen fluoride-pyridine over 1.5
hours. The reaction mixture was diluted with ethyl acetate (200 ml),
washed with a 10% potassium hydrogen sulfate solution, brine and a dilute
sodium bicarbonate solution, dried over anhydrous sodium sulfate and
evaporated in vacuo to give a gum. This gum was chromatographed on a
column of silica gel (Baker 60-200 mesh, 300 g), eluting with ethyl
acetate-hexane (35:65 and 1:1) to give 6.0 g (85.4%) of Compound 1E as a
solid (m.p. 73-77.degree.) with consistent .sup.1 H-NMR and .sup.13 C-NMR
spectra.
1F. [1S-[1.alpha.,3.alpha.,4a.alpha.,7.beta.,8.beta.(2S*, 4S*),
8a.beta.]]-2,2-Dimethylbutanoic acid,
decahydro-3-hydroxy-methyl-8-[2-[tetrahydro- 6-oxy-4-[(phenyl-methoxy)
methoxy]-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
To a chilled (ice bath) and stirred solution of Compound 1E (500 mg, 0.92
mmol) in dry dichloromethane (5 ml) under an atmosphere of nitrogen was
added dropwise 2,6-lutidine (642 .mu.l, 5.51 mmol), followed dropwise by
trifluoromethane sulfonic anhydride (232 .mu.l, 1.38 mmol). The mixture
was stirred for 30 minutes, quenched with water (1.0 ml), warmed up to
room temperature, diluted with a 10% potassium bisulfate solution (20 ml)
and extracted with ethyl acetate (3.times.20 ml). The combined ethyl
acetate extracts were washed with a 10% potassium bisulfate solution, a
dilute sodium bicarbonate solution and brine, dried over anhydrous sodium
sulfate and evaporated in vacuo to give a gum. This was chromatographed on
a column of Merck Kieselgel-60.RTM. (150 g) eluting with ethyl
acetate-hexanes (1:3 and 4:6) to give 245 mg (49%) of Compound 1F as a gum
with consistent .sup.1 H-NMR and .sup.13 C-NMR spectra.
1G. [1S-[1.alpha.,3.alpha.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),
8a.beta.]]-2,2-Dimethylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-[tetrahydro-4-hydroxy-oxo-2H-pyran-2-yl]
ethyl]-1-naphthalenyl ester
A slow stream of hydrogen was bubbled for 2.0 hours through a solution of
Compound 1F (240 mg, 0.441 mmol) in ethyl acetate (6 ml) containing 20%
palladium hydroxide on carbon (150 mg) at room temperature. The mixture
was then filtered through a bed of celite.RTM. and washed with a small
amount of ethyl acetate. The filtrate and washings were combined and
evaporated in vacuo to give a gum. This was chromatographed on a column of
silica gel (Baker 60-200 mesh, 50g) eluting with acetate-hexanes (1:3) to
give 145 mg (77.5%) of Example 1 as a solid with consistent .sup.1 H-NMR
and .sup.13 C-NMR spectra.
EXAMPLE 2
[1S-[1.alpha.(.beta.S*,.DELTA.S*),2.alpha.,4.alpha..beta.,6.beta.,8.beta.,8
.alpha..alpha.]]Decahydro-.beta.,
.DELTA.,6-trihydroxy-2-methyl-8-(1,1-dimethylpropycarbonyloxy)
-1-naphthalene heptanoic acid, monolithium salt
A stirred solution of Example 1 (140 mg, 0.33 mmol) in tetrahydrofuran (3
ml) at room temperature under an atmosphere of nitrogen was treated with
1.0 N lithium hydroxide (660 .mu.l, 0.66 mmol). After 30 minutes, the
solvent was evaporated by a stream of nitrogen to leave a gummy residue.
This residue was dissolved in water and chromatographed on a column of
HP-20 (1.5".times.1" column bed) eluting with deionized, distilled water
(250 ml) and 50% methanol-water (250 ml) to give in the later eluate
TLC-homogeneous Example 2. This eluate was evaporated in vacuo and
lyophilized overnight to give 130 mg (87.9%) of a hydrated analytical
specimen of Example 2 as a white solid with consistent IR, mass and .sup.1
H-NMR spectral data.
Anal. for C.sub.24 H.sub.41 O.sub.7 Li. 0.75 H.sub.2 O (MW=462.04): Calc'd:
C, 62.38, H, 9.27; Found: C, 62.41; H, 9.15.
IR Spectrum (KBr): .mu.Max 3424, Cm-.sup.1 : (OH), 1715 Cm-.sup.1
(C=O,ester), 1583 Cm-.sup.1 (C=0, salt) etc.
Mass Spectrum: m/e (m+Li).sup.+ =469, (m-H).sup.- =461, (m+2Li-H).sup.+
=655, (m+Li-2H) =467, (m+3Li-2H).sup.+ =461, (m+2Li-3H).sup.- =453, etc.
H.sup.1 -NMR Spectrum (270 mHz, D.sub.20): .delta.6 0.77 (t+d,6H,CH.sub.3),
1.00 (s,3H,CH.sub.3), 1.02 (S,3H,CH.sub.3), 2.28 (m,2H,CH.sub.2 C=O), 3.65
(m,1H,CH--OH), 4.04 (m,2H,CHOH+CHOH), and 5.08
##STR16##
EXAMPLE 3
[1S-[1.alpha.,3.beta.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2-Methy
lbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y
l) ethyl]-1-naphthalenyl ester, partially racemized
3A. [1S-[1.alpha.(R*),3.beta.,4a.alpha.,7.beta.,
8.beta.(2S*,4S*),8a.beta.]]-2-Methylbutanoic acid,
3-[[(1,1-dimethyl-ethyl)dimethylsilyl]oxy]decahydro-7-methyl-8-[2-(tetrahy
dro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester
To a degassed, argon-purged solution of 9.38 g (18.0 mmol) of intermediate
IA in 200 ml of ethyl acetate was added 1.4 g of 10% platinum on carbon.
This suspension was subjected to 50 psi of H.sub.2 in a Parr hydrogenation
apparatus for 14.5 hours. Thin layer chromatography analysis indicated the
complete consumption of intermediate 1A with generation of intermediate 3A
and a by-product. The filtered reaction mixture was concentrated, and the
products were isolated by flash chromatography. Elution with 45% hexanes
in ethyl acetate gave 7.73 g (82%) of intermediate B as a clear glass.
3B. [1S-[1.alpha.(R*), 3.beta.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),
8a.beta.]]-2-Methylbutanoic acid,
3-[[(1,1-dimethylethyl)]oxy]decahydro-7-methyl-8-[2-[tetrahydro-6-oxo-4-[(
phenylmethoxy)-methoxy]-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
The generation of benzyloxymethyl bromide was carried out by bubbling
hydrobromide through a methylene chloride solution of benzyloxymethyl
chloride for 15 minutes at 0.degree. C., followed by stirring at ambient
temperature for 45 minutes and exhaustively stripping in vacuo all
volatiles.
To a solution of 23.1 g (115 mmol, 2.42 eq) of benzyloxymethyl bromide in
40 ml of methylene chloride at 0.degree. C. was added 15.6 ml (123 mmol,
2.60 eq) of N,N-dimethylaniline and a solution of 24.9 g (47.4 mmol, 1.0
eq) of intermediate 3A in 50 ml of methylene chloride. This mixture was
brought immediately to ambient temperature and stirred for 18 hours. The
reaction mixture was then diluted with 400 ml of ethyl acetate, washed
sequentially with saturated aqueous copper sulfate (1.times.200 ml,
1.times.75 ml) and brine (1.times.150 ml), dried with magnesium sulfate
and concentrated. The product was isolated by elution from silica gel with
10% ethyl acetate in hexanes, yielding 29.4 g (96.1%) of intermediate 3B
as a clear, colorless, viscous oil.
3C.
[1S-[1.alpha.(R*),3.beta.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2-
Methylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-[tetrahydro-6-oxo-4-[(phenylmethoxy)meth
oxy]-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
A solution of 28.8 g (44.7 mmol) of intermediate 3B in 400 ml of
acetonitrile was cooled at -20.degree. C. under argon and treated with
three 10 ml portions of HF-pyridine over 2 hours, with warming to
0.degree. C. after 1.5 hours. The reaction mixture was diluted with 500 ml
of ethyl acetate and washed sequentially with saturated copper sulfate
(aqueous 2.times.150 ml), brine (1.times.250, 200 and 150 ml) and
saturated sodium bicarbonate (aqueous, 2.times.250 ml, 1.times.200 ml).
After drying the ethyl acetate solution with sodium sulfate and
concentrating, the crude product was purified by silica gel
chromatography, eluting with 40% hexanes in ethyl acetate to yield 2.2 g
(93.7%) of intermediate 3C as a clear, colorless oil.
[1S-[1.alpha.,3.alpha.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2-Meth
ylbutanoic acid, decahydro-3-hydroxy-7-methyl-8-[2
-[tetrahydro-6-oxo-4-[(phenylmethoxy)
methoxy]-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester, partially racemized
To a chilled (0.degree. ice bath) and stirred solution of Compound 3C (3.78
g, 7.14 mmol) in dichloromethane (30 ml) under an atmosphere of nitrogen
was added dropwise 2,6-lutidine (5.02 ml, 43.2 mmol). After 15 minutes,
trifluoromethane sulfonic anhydride (1.78 ml, 10.7 mmol) was added
dropwise. The mixture was stirred for 30 minutes, quenched with water (3
ml), warmed up to room temperature, diluted with a 10% potassium bisulfate
solution (75 ml) and extracted with ethyl acetate (2.times.150 ml). The
combined ethyl acetate extracts were washed with a 10% potassium bisulfate
solution twice, a 5% sodium bicarbonate solution twice and brine, dried
over anhydrous sodium sulfate and was evaporated in vacuo to give a gum.
This was chromatographed on a column of Merck Kieselgel-60.RTM. (250 g),
eluting with ethyl acetate-hexane (3:7 and 4:6) to give 1.25 g (33.1%) of
thin-layer chromatography-homogeneous compound 3D as a gum, with
consistent H.sup.1 -NMR and C.sup.13 -NMR spectra.
[1S-[1.alpha.,3.alpha.,4a.alpha.,7.beta.,8.beta.(2S*,4S*),8a.beta.]]-2-Meth
ylbutanoic acid,
decahydro-3-hydroxy-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y
l)ethyl]-1-naphthalenyl ester, partially racemized
A slow stream of hydrogen was bubbled through a solution of Compound 3D
(100 mg, 0.188 mmol) in ethyl acetate (3 ml) containing 20% palladium
hydroxide on carbon (50 mg) at room temperature for 1.0 hours, with
monitoring of aliquots by thin-layer chromatography. It was then filtered
through a bed of Celite.RTM. and washed with a small amount of ethyl
acetate. The filtrate and washings were combined and evaporated in vacuo
to give a gum. This was chromatographed on a column of silica gel (15 g,
Baker 60-200 mesh) eluting with ethyl acetate-dichloromethane (3:7) to
give 68 mg (87.9%) of thin-layer chromatography homogeneous Example 3 as a
gum with consistent H.sup.1 -NMR and C.sup.13 -NMR spectra Another run
using 120 mg of Compound 3D gave 82 mg more of Example 3.
EXAMPLE 4
[1S-[1.alpha.(.beta.S*,.DELTA.dS*),2.alpha.,4.alpha..beta.,6.beta.,8.beta.,
8a.alpha.]]-Decahydro-.beta.,.DELTA.,6-trihydroxy-2-methyl-8-(1-methylpropy
lcarbonyloxy)-1-naphthaleneheptanoic acid, monolithium salt
A stirred solution of Example 3 (135 mg, 0.329 mmol) in tetrahydrofuran (4
ml) at room temperature under an atmosphere of nitrogen was treated with
1.0 N lithium hydroxide (411 ml, 0.411 mmol). After 1.0 hour, the solvent
was evaporated by a stream of nitrogen to give a gum. This gum was
dissolved in water and chromatographed on a column of HP-20
(1.5".times.1.0" column bed) eluting with deionized, distilled water
(about 250 ml) and 50% methanol-water (about 250 ml) to give in the later
eluate thin-layer chromatography-homogeneous Example 4. This eluate was
evaporated in vacuo and lyophilized overnight to give 110 mg (77%) of a
hydrated analytical specimen of Example 4 as a white solid with consistent
IR, mass and H.sup.1 -NMR spectral data.
Anal. for C.sub.23 H.sub.39 O.sub.7 Li.0.3 H.sub.2 O (MW:434.50+0.3 H.sub.2
O):
Calc'd: C, 62.80; H, 9.07;
Found: C, 62.71; H, 9.10;
IR Spectrum (KBr): .mu.Max 3424 Cm-.sup.1 (OH), 1718 and 1707 Cm-.sup.1
(C=0,ester), 1583 Cm-.sup.1 (C=0,acid salt), etc.
Mass Spectrum: m/e (m-H).sup.- =427, (m+Li).sup.+ =635, (m+Li-2H).sup.-
=633, (m-2Li-H).sup.+ =661, etc.
H.sup.1 -NMR Spectrum (270 MHz, D.sub.20): .delta.0.75
(d,3H,J=7.0,CH.sub.3), 0.81, 0.82 (2t,3H,J=.about.7.6,CH.sub.3), 1.05
(d,3H,J=.about.7.0,CH.sub.3), 3.65 (m,1H,CH--OH), 4.05 (m,2H,CHOH+CH+OH),
5.07
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